Dis Model Mech. 2023 Jun 1;16(6):dmm049854. doi: 10.1242/dmm.049854

NR2F1 shapes mitochondria in the mouse brain, providing new insights into Bosch-Boonstra-Schaaf optic atrophy syndrome

Sara Bonzano1,2, Eleonora Dallorto1,2, Ivan Molineris1,3, Filippo Michelon1,2, Isabella Crisci1,2, Giovanna Gambarotta2,4, Francesco Neri1,3, Salvatore Oliviero1,3, Ruth Beckervordersandforth5, Dieter Chichung Lie5, Paolo Peretto1,2, Serena Bovetti1,2, Michèle Studer6, Silvia De Marchis1,2

1Department of Life Sciences and Systems Biology (DBIOS), University of Turin, Via Accademia Albertina 13, Turin 10123, Italy.
2Neuroscience Institute Cavalieri Ottolenghi (NICO), Regione Gonzole 10, Orbassano 10043, Italy.
3IIGM Foundation-Italian Institute for Genomic Medicine, Sp142 Km 3.95, Candiolo 10060, Italy.
4Department of Clinical and Biological Sciences (DSCB), Regione Gonzole 10, Orbassano 10043, Italy.
5Institut für Biochemie, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Fahrstrasse 17, Erlangen 91054, Germany.
6Institute de Biologie Valrose (iBV), Université Côte d’Azur (UCA), CNRS 7277, Inserm 1091, Avenue Valrose 28, Nice 06108, France.


The nuclear receptor NR2F1 acts as a strong transcriptional regulator in embryonic and postnatal neural cells. In humans, mutations in the NR2F1 gene cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including vision impairment, intellectual disability and autistic traits. In this study, we identified, by genome-wide and in silico analyses, a set of nuclear-encoded mitochondrial genes as potential genomic targets under direct NR2F1 transcriptional control in neurons. By combining mouse genetic, neuroanatomical and imaging approaches, we demonstrated that conditional NR2F1 loss of function within the adult mouse hippocampal neurogenic niche results in a reduced mitochondrial mass associated with mitochondrial fragmentation and downregulation of key mitochondrial proteins in newborn neurons, the genesis, survival and functional integration of which are impaired. Importantly, we also found dysregulation of several nuclear-encoded mitochondrial genes and downregulation of key mitochondrial proteins in the brain of Nr2f1-heterozygous mice, a validated BBSOAS model. Our data point to an active role for NR2F1 in the mitochondrial gene expression regulatory network in neurons and support the involvement of mitochondrial dysfunction in BBSOAS pathogenesis.

DOI: 10.1242/dmm.049854